Memantine for the treatment of mild and mild to moderate Alzheimer&#39;s disease

ABSTRACT

The present invention provides a method for the treatment, prevention, or delay of progression of mild, or mild-to-moderate Alzheimer&#39;s disease, by administering an effective dose of memantine. The present invention also provides a method for preventing the decrease in glucose metabolism in the cortical and sub-cortical regions of the brain in subjectes with mild, or mild-to-moderate Alzheimer&#39;s disease.

This application claims priority from U.S. Provisional Application Ser.Nos. 60/534,553, filed Jan. 5, 2004, and 60/542,176, filed Feb. 4, 2004,the disclosures of which are incorporated herein in their entirety.

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIELD OF THE INVENTION

The present invention relates to a method of treating individualssuffering from mild-to-moderate dementia of the Alzheimer's type byadministering an effective amount of memantine. The present inventionalso relates to a method of preventing decreases in the glucosemetabolic rate associated with regression in Alzheimer's disease inindividuals suffering from mild-to-moderate dementia

BACKGROUND OF THE INVENTION

Dementia and Alzheimer's Disease

Dementia is a serious disorder affecting as many as 10% of individualsolder than 65 years and more than 24% of those older than 85 years(Hofman et al., Int. J. Epidemiol. 1991; 20:736-748; Jorm and Jolley,Neurology. 1998; 51:728-733; Lobo et al., Neurology. 2000; 54(Suppl.5):S4-S9). Alzheimer's disease (AD) is an increasingly prevalent form ofneurodegeneration that accounts for approximately 50%-60% of the overallcases of dementia among people over 65 years of age. Dementia associatedwith AD is referred to as senile dementia of the Alzheimer's type(SDAT), in common usage with Alzheimer's disease. AD is characterizedclinically by progressive loss of memory, cognition, reasoning,judgment, and emotional stability that gradually leads to profoundmental deterioration and ultimately, death. AD is a progressive disorderwith a mean duration of around 8.5 years between onset of clinicalsymptoms and death. AD is believed to represent the fourth most commonmedical cause of death and affects about 4-5 million people in theUnited States. Prevalence of AD doubles every 5 years beyond age 65(National Institute on Aging: Prevalence and costs of Alzheimer'sdisease. Progress Report on Alzheimer's Disease. NIH Publication No. 993616, November 1998; Polvikoski et al., Neurology. 2001; 56:1690-1696).AD currently affects about 15 million people world-wide (including allraces and ethnic groups) and owing to the relative increase of elderlypeople in the population its prevalence is likely to increase over thenext two to three decades. AD is at present incurable. No treatment thateffectively prevents AD or reverses its symptoms and course is currentlyknown.

Neuronal Death. AD is associated with death of pyramidal neurons andloss of neuronal synapses in brain regions associated with higher mentalfunctions (Francis et al., J. Neurol. Neurosurg. Psychiatry. 1999;66:137-147). The brains of individuals with AD exhibit characteristiclesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloiddeposits in blood vessels) and neurofibrillary tangles. Smaller numbersof these lesions in a more restricted anatomical distribution are alsofound in the brains of most aged humans who do not have clinical AD.Amyloid plaques and amyloid angiopathy also characterize the brains ofindividuals with Trisomy 21 (Down's Syndrome) and Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, adefinitive diagnosis of AD usually requires observing the aforementionedlesions in the brain tissue of patients who have died with the diseaseor, rarely, in small biopsied samples of brain tissue taken during aninvasive neurosurgical procedure. Nevertheless, physicians routinelydiagnose AD based on a battery of symptoms, relying on the knowncorrelation between such symptoms and the symptomology obtained onbiopsy.

AD is associated with a profound loss of cholinergic neurons within thenucleus basalis of Meynert (Perry et al., Br. Med. J. 1978; 2:1456-1459;Geula and Mesulam, Cholinergic systems and related neuropathologicalpredilection patterns in Alzheimer disease. In: Alzheimer's Disease.Terry et al. eds.; New York: Raven Press; 1994, pp. 263-291). Thesignaling in these neurons is mediated by the extracellularly releasedneurotransmitter acetylcholine (ACh). Drugs that selectively enhancecholinergic function by inhibition of the cholinergic catabolic enzymeacetylcholinesterase (AChE), which destroys ACh after the latter hasbeen secreted into the synaptic clefts (Goff and Coyle, Am. J.Psychiatry. 2001; 158: 1367-1377) have been used to treat AD. Atpresent, the most widely clinically used acetylcholinesterase inhibitors(ACHEI) are donepezil, galantamine, and rivastigmine.

Dementia and Metabolism. Structural neuroimaging has an important rolein initial evaluation of dementia for ruling out potentially treatablecauses. Dementia associated with AD is distinguished from other forms ofdementia by a characteristic bilateral pattern of decreased metabolismthat is most prominent in temporal, parietal and prefrontalassociational areas, and also in the posterior cingulate and precuneus,with relative sparing of primary sensory and motor cortices, basalganglia, thalamus, brainstem, and cerebellum (Small & Leiter, J ClinPsychiatry. 1998; 59 Suppl 11: 4-7). The severity of decline in glucosemetabolic rate parallels the severity of dementia and correlates withregional neuronal loss (McGeer et al., Can J Neurol Sci. 1986; 13(4Suppl):511-6). The brain regions most affected by Alzheimer's diseasechange over time. ¹⁸F-flurodeoxyglucose positron emission tomography(FDG PET) in vivo metabolic studies have demonstrated hypometabolism inwidespread cortical areas, including frontal and temporal lobe andhippocampal area, beginning in the early stages of AD. FDG PET measuresregional blood flow and/or glucose metabolism and is hypothesized tohave the capacity to detect functional abnormalities before structuralchanges appear (Ichimiya et al., Psychiatry Clin Neurosci. 1998; 52Suppl: S223-5; Reiman et al., Proc Natl Acad Sci USA. 2001 13; 98(6):3334-9; Silverman et al., J Nucl Med. 2002; 43(2): 253-66; Small et al.,Curr Neurol Neurosci Rep. 2003; 3(5): 385-92).

NMDA-Receptor Antagonists and Memantine

The excessive or pathological activation of glutamate receptors,particularly those that are selectively activated byN-methyl-D-aspartate (NMDA), has also been implicated in the processesthat underlie the degeneration of cholinergic cells in the brains of ADpatients (Greenamyre et al., Neurobiol. Aging. 1989; 10:593-602; Franciset al., J. Neurochem. 1993; 60:263-291; Li et al., J. Neuropathol. Exp.Neurol. 1997; 56:901-911; Wu and Rowan, Neuroreport. 1995; 6:2409-2413).The NMDA receptor is pivotal for several physiologic synaptic plasticityprocesses including memory and learning (Collinridge and Singer, TrendsPharmacol. Sci. 1990; 11: 290-296).

NMDA receptor antagonists potentially have a wide range of therapeuticapplications in numerous CNS disorders such as acute neurodegeneration(e.g., associated with stroke and trauma), chronic neurodegeneration(e.g., associated with Parkinson's disease, AD, Huntington's disease,and amyotrophic lateral sclerosis [ALS]), epilepsy, drug dependence,depression, anxiety, and chronic pain (for reviews see: Parsons et al.,Drug News Perspect. 1998; 11:523-569; Parsons et al., 1999, supra;Jentsch and Roth, Neuropsychopharmacology. 1999; 20: 201-205; Doble,Therapie. 1995; 50: 319-337). Functional inhibition of NMDA receptorscan be achieved through actions at different recognition sites withinthe NMDA receptor complex. Such sites include i) the primary transmittersite (competitive); ii) the phencyclidine site located inside the cationchannel (uncompetitive); iii) the polyamine modulatory site, and iii)the strychnine-insensitive, co-agonistic, allosteric, glycine site(glycine B) (Parsons et al., 1999, supra).

It is believed that the excitatory neurotransmitter glutamate plays animportant role in the pathophysiology (as opposed to etiology) ofneurodegenerative diseases such as AD, Parkinsons's disease, andamyotrophic lateral sclerosis. About 70% of all excitatory synapses inthe CNS are stimulated by glutamate, and dysfunctional, chronic releaseof glutamate can produce a prolonged excitatory effect via glutamatereceptor activation. This prolonged activation is mediated by the NMDAglutamate receptor and can result in the degeneration and death ofcortical neurons.

Memantine (1-amino-3,5-dimethyl adamantane) is an analog of1-amino-cyclohexane (disclosed, e.g., in U.S. Pat. Nos. 4,122,193;4,273,774; 5,061,703) which is a systemically-active uncompetitive NMDAreceptor antagonist having moderate affinity for the receptor, strongvoltage dependency and rapid blocking/unblocking kinetics. Memantine andother 1-aminoalkylcyclohexanes have proven useful in alleviation ofvarious progressive neurodegenerative disorders such as dementia inpatients with moderate to severe AD, Parkinson's disease, and spasticity(see, e.g., U.S. Pat. Nos. 5,061,703; 5,614,560, and 6,034,134; Parsonset al., 1999, supra; Möebius, ADAD. 1999; 13:S172-178; Danysz et al.,Neurotox. Res. 2000; 2:85-97; Winblad and Poritis, Int. J. Geriatr.Psychiatry. 1999; 14:135-146; Görtelmeyer et al. 1992, supra; Danysz etal., Curr. Pharm. Des. 2002;,8:835-843; Jirgensons et. al., Eur. J. Med.Chem. 2000; 35: 555-565).

Memantine is currently approved in Europe for the treatment ofmoderately severe to severe AD, and in the United States for thetreatment of moderate to severe AD. In addition, memantine when given tomoderate to severe AD patients maintained on the AChEI donepezilresulted in unexpected greater relief of symptoms, compared to ADpatients receiving placebo. This effect has not been demonstrated inpatients with mild to moderate AD, where combination therapy involvingadministration of memantine and the AChEIs did not result in any benefitcompared with the AChEI alone.

SUMMARY OF THE INVENTION

The present invention provides a method for the treatment ofmild-to-moderate Alzheimer's disease by administering an effectiveamount of memantine.

In one embodiment, memantine is administered in a range from about 5-100mg/day.

In another embodiment, memantine is administered in a range from about10-40 mg/day.

In yet another embodiment, memantine is administered at a dose of about20 mg/day.

In a further embodiment, memantine is administered to patients withmild-to-moderate Alzheimer's disease who have previously taken, butdiscontinued, AChEI inhibitors such as donepezil.

In yet another embodiment, memantine is administered to patients withmild Alzheimer's disease.

The present invention also provides a method of preventing the decreasein glucose metabolism in the cortical and sub-cortical regions of thebrain in subjects with mild-to-moderate AD by administering an effectiveamount of memantine.

In one embodiment, memantine is administered in a range from about 5-100mg/day.

In another embodiment, memantine is administered at a dose of about 20mg/day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. FIG. 1 demonstrates differences in regional brain metabolicactivity assessed by PET in mild-to-moderate AD subjects following 24weeks of placebo compared to baseline. Mean levels of relative metabolicactivity are superimposed on a standard surface rendering template fromSPM. Red indicates higher levels of metabolic activity followingplacebo; blue indicates lower levels of activity. Statisticallysignificant (p<0.025) regional differences are determined with a10-voxel extent threshold to adjust for multiple comparisons. Images aand b represent the lateral cortical surfaces; images c through i areaxial images (z=−31 mm, −19 mm, −8 mm, 8 mm, 14 mm, 29 mm, 60 mmrelative to the AC-PC line, respectively); image j is a sagittal imageat +33 mm (right side of brain). The x, y, and z coordinates correspondto Talairach space.

FIG. 2. FIG. 2 demonstrates differences in regional brain metabolicactivity assessed by PET in AD subjects following 24 weeks of 20 mgmemantine per day compared to baseline. Red indicates higher levels ofmetabolic activity following Memantine; blue indicates lower levels ofactivity. Statistically significant (p<.025) regional differences aredetermined with a 10-voxel extent threshold to adjust for multiplecomparisons. Image descriptions are the same as those given in FIG. 1,except that image j is a sagittal image at −4 mm (left side of brain).

DETAILED DESCRIPTION

The present invention unexpectedly demonstrates that patients withmild-to-moderate senile dementia of the Alzheimer's type (SDAT) benefitfrom treatment with memantine compared with placebo. This result issurprising in view of a previous study in which addition of memantine toan AChEI administration regimen did not demonstrate improved efficacycompared with AChEI therapy alone for the treatment of mild-to-moderateAD. The present result is unexpected for the further reason that themajority of the patient population treated with memantine wereindividuals who were previously treated with AChEI but either haddiscontinued AChEI therapy either because they did not respond, orbecause they could not tolerate the adverse side effects, or both.

The present invention is based on results from a randomized,double-blind, placebo-controlled, multi-center, parallel-group studycomparing memantine to placebo in outpatients diagnosed with probable ADaccording to NINCDS-ADRDA criteria. Severity of mild to moderate wasestablished using the Mini-Mental State Examination (MMSE) score (≧10and ≦22; 0 is the lowest score and 30 is the highest score).

The present invention also unexpectedly demonstrates that memantineadministered to patients with mild-to-moderate AD prevents the reductionof glucose metabolism in the cortical and subcortical regions of suchpatients relative to placebo. These data are based on results from PETscanning procedures in 10 patients (5 on memantine and 5 on placebo) atone site of the multi-center trial described above.

In the study of the present invention, there were approximately 400patients enrolled across 42 centers. Evaluation of primary efficacy wasachieved by Alzheimer's Disease Assessment Scale-cognitive subscale(ADAS-cog) and the Clinician's Interview-Based Impression of Changeincluding caregiver information (CIBIC-plus). Secondary efficacy wasdetermined using Alzheimer's disease Cooperative Study-Activities ofDaily Living (ADCS-ADL) and Neuropsychiatric Inventory (NPI) criteria.

The ADAS-cog comprises an 11-item scale that is used to assess theseverity of selected areas of cognitive impairment (memory, language,orientation, reason and praxis). Scores range from 0 to 70 with lowerscores indicating lesser severity and a score of 70 representing theworst cognitive impairment. Its use in assessing and following changesin patients with mild to moderate Alzheimer's disease has beenextensively validated. The ADAS-cog was administered at each clinicvisit starting with the Baseline visit and at the end of weeks 4, 8, 12,18 and 24 (or upon early termination).

The CIBIC-Plus is a global rating that was derived through anindependent, comprehensive interview with the patient and caregiver byan experienced rater/clinician who was barred from knowledge of allother psychometric test scores (after Baseline visit) conducted as partof this protocol and who is not otherwise familiar with the patient.Scores 1-3 indicate improvement; Score 4 indicates no change (ascompared to baseline); Scores 5-7 indicate worsening. The CIBIC raterassessed disease severity at Baseline. Using the results from Baselinefor reference, the rater then interviewed the patient and caregiver atthe end of Weeks 4, 8, 12, 18 and 24 (or upon early termination), toobtain an “Impression of Change” rating. The format for this scale wasderived from the Alzheimer's Disease Cooperative Study—Clinician'sGlobal Impression of Change scale (ADCS-CGIC) (Schneider, L. et al,Alzheimer Dis Assoc Disord. 1997; 11 Suppl 2:S22-32). The CIBIC-plus wasadministered at each clinic visit starting with the Baseline visit.

The ADCS-ADL inventory consists of 23 questions used to measure thefunctional capabilities of patients with dementia. These questions areselected from a larger set of 49 questions in the original ADL scale. Amore common selection is of 19 questions from the same 49 questiongroup. Each ADL item comprises a series of hierarchical sub-questions,ranging from the highest level of independent performance of each ADL tocomplete loss. The ADSC-ADL Inventory total score ranges from 0 (lowerfunctioning status) to 78 (higher functioning status). A higher scoreindicates a better functioning status. The inventory is performed byinterviewing a person who is in close contact with the patient andcovers the most usual and consistent performance of the patient over thepreceding four weeks (Galasko et al., Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9). The ADCS-ADL was administered at each clinic visitstarting with the Baseline visit.

The NPI is a validated scale that assesses behavioral disturbances inpatients with dementia (Cummings et al., Neurology. 1994;44(12):2308-14). It provides both a total score (sum of 12 domainscores) as well as scores for each subscales (e.g., delusions,hallucinations, agitation/aggression, depression/dysphoria, anxiety,disinhibition, elation/euphoria, apathy/indifference,irritability/lability, aberrant motor activity). For each subscale, boththe frequency and the severity of each behavior is measured. The NPItotal score ranges from 0 (higher functioning status) to 144 (lowerfunctioning status). The NPI is based upon responses from the caregiver.The NPI was administered at Baseline and the end of Weeks 12 and 24 (orupon early termination).

After 24 weeks, statistically significant improvement was shownaccording to the ADAS-cog, CIBIC-plus, and NPI overall criteria.

DEFINITIONS

“Memantine” refers to 1-amino-3,5-dimethyladamantane or pharmaceuticallyacceptable salts, such as the hydrochloride salt. In the United States,the trade name for memantine is Namenda®, in Germany Akatinol and in theEuropean Union Auxura, and Ebixa. Memantine is the subject matter ofU.S. Pat. Nos. 4,122,193 and 4,273,774.

Various salts and isomers (including stereoisomers and enantiomers) ofmemantine can be used. The term “salts” can include acid addition saltsor addition salts of free bases. Examples of acids which may be employedto form pharmaceutically acceptable acid addition salts includeinorganic acids such as hydrochloric, sulfuric, or phosphoric acid, andorganic acids such as acetic, maleic, succinic, or citric acid, etc. Allof these salts (or other similar salts) may be prepared by conventionalmeans. The nature of the salt is not critical, provided that it isnon-toxic and does not substantially interfere with the desiredpharmacological activity. A preferred salt for the method of the presentinvention is the hydrochloride salt.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions (toxicity or side effects)when administered to a mammal (e.g., human). Preferably, as used herein,the term “pharmaceutically acceptable” means approved by a regulatoryagency of the Federal or a state government or listed in the U.S.Pharmacopeia or other generally recognized pharmacopeia for use inmammals, and more particularly in humans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound (e.g., an 1-aminocyclohexane derivative) isadministered. Such pharmaceutical carriers can be sterile liquids, suchas water, saline solutions, aqueous dextrose solutions, aqueous glycerolsolutions, and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Suitable pharmaceutical carriers are described in“Remington's Pharmaceutical Sciences” by E. W. Martin, 18^(th) Edition.

The term “patient” or “subject in need thereof” as used herein refers toa mammal. In particular, the term refers to humans diagnosed withmild-to-moderate AD. In particular, the term refers to humans diagnosedwith mild-to-moderate AD who also demonstrate reductions in glucosemetabolic rate (GMR) compared to individuals without AD.“Mild-to-moderate senile dementia of the Alzheimer's type” (SDAT), ormild-to-moderate Alzheimer's can be diagnostically assessed as “probableAlzheimer's” according to the National Institute of Neurological andCommunicative Disorders and Stroke/the Alzheimer's Disease and RelatedDisorders Associations (NINCDS-ADRDA) criteria, described above, and inthe Examples below. The NINCDS-ADRDA criteria for probable Alzheimer'sare provided in Example 1.

The diagnosis of “mild-to-moderate” is well within the purview of theordinary skilled physician using standard criteria, including theclinical assessment scales disclosed above and below. By way of example,the following numerical ranges on the standardized Mini-Mental StateExamination (MMSE; 0-30 scale) have been used to diagnosemild-to-moderate, moderate, and moderate-to-severe Alzheimer's.

Mild-to-moderate AD has been diagnosed as determined by MMSE scores of10 to 22 in the present study, and also from 10-26 in studies usingother therapeutics for treating mild-to-moderate Alzheimer's (e.g.,donepezil). Moderate-to-severe Alzheimer's has been diagnosed insubjects having MMSE scores from 3 to 14, or 5 to 14.

Accordingly, a diagnosis of “mild” Alzheimer's disease could be made forsubjects having the higher scores within the above-described ranges,e.g., about 15 to 26 on the MMSE, preferably about 15-22. MildAlzheimer's also has been diagnosed within an MMSE range of 18-22.

The above is contrasted with severe Alzheimer's disease, which has beendetermined by scores of 5 to 9 on the MMSE. Severe Alzheimer's has alsobeen diagnosed when the MMSE score was less than 10.

It should be noted that the MMSE scale is not the only way to diagnosemild Alzheimer's disease, but represents a convenience. Nor should theclaims be construed as requiring the step of “grading” a patient on theMMSE scale to be performed. Thus a patient having mild Alzheimer'sdisease is a patient who would score 15 or higher if the patient werescored according to MMSE scale. If a different scale were to be used,“mild” AD would be defined as a diagnosis of AD or probable AD which ismade based on a score that clearly does not overlap with the score rangefor moderate-to-severe AD established for the same scale.

The term “treat” is used herein to mean to relieve or alleviate at leastone symptom of a disease in a subject. For example, in relation todementia, the term “treat” may mean to relieve or alleviate cognitiveimpairment (such as impairment of memory and/or orientation) orimpairment of global functioning (activities of daily living) and/orslow down or reverse the progressive deterioration in ADL or cognitiveimpairment in individuals having mild-to-moderate SDAT.

Within the meaning of the present invention, the term “treat” alsodenotes inhibition, i.e., prevention of or delay of the progression of,disease in the patients presenting with additional symptoms associatedwith SDAT, such as but not limited to those identified using one or moreof the ADAS-cog and CIBIC-plus criteria, the ADCS-ADL criteria, or theNPI total criteria, defined above. The term “delay the progression” isused herein to mean slower than expected development or continuance oraggravation of a disease in a subject compared to an untreated subject.This can be determined for Alzheimer's disease, for example, byobtaining slower than expected deterioration in measures such ascognitive performance in treated patients, compared with those measuresin untreated patients (who represent the expected progression of thedisease). Cognitive performance can be measured using, e.g., theAlzheimer's Disease Assessment Scale (ADAS-cog), or the Alzheimer'sDisease Cooperative Study-Activities of Daily Living (ADCS-ADL). Forexample, the typical disease progression in subjects with mildAlzheimer's disease is an increase of about 1 to about 3 points on the.ADAS-cog over a time period of about 6 months. However, diseaseprogression is highly individualized, and also depends on factors suchas the initial condition of the patient. Thus, the expected slope ofdeterioration will be “flatter” for a patient who is in good physicalcondition and has only mild impairment than that of a patient who is inpoorer physical condition and has more pronounced impairment, even ifboth patients are scored as suffering from “mild” Alzheimer's disease.This is appreciated by those skilled in the art.

In a specific embodiment, the term “treat” also means to increase theglucose metabolic rate, or to inhibit further reduction in the metabolicrate in the cortical and sub-cortical regions of brains in patients withmild-to-moderate AD, which is associated with regression. This can alsobe assessed by comparing the glucose metabolism in treated patients withthat in untreated patients. A reduction in the decrease of glucosemetablolism in the treated patients, or a slower than expected decrease,or stability of glucose metabolism in treated patients, compared withuntreated patients, is indicative of a benefit accompanying thetreatment. This can be determined, e.g., by positron emission tomography(PET) scans, or as calculated, e.g., by superimposition on a standardsurface template and statistically determined using statisticalparametric mapping. However, any known technique in the pertinent artcan be used to assess changes in glucose metabolism, includinghigh-resolution MRI.

The term “prophylactically treat” also means prophylactic use ofmemantine in a subject to avert behavior or events associated with SDATin mild-to-moderate AD. Subjects having or at risk for developing AD,such as those with a familial pattern of AD, can be identified bydiagnostic or prognostic assays according to the ordinary skill in theart. In a specific embodiment, the term “prophylactically treat” refersto inhibition (i.e., prevention , delay or alleviation) of the reductionin glucose metabolism in the cortical and sub-cortical regions of brainsin individuals with mild-to-moderate AD or individuals who present withthis symptom without otherwise fulfilling the criteria for a definitiveor even tentative diagnosis of AD.

The term “therapeutically effective amount” is used herein to mean anamount or dose of memantine that is effective to ameliorate, delay, orprevent a symptom, behavior or event associated with SDAT in patientswith mild-to-moderate AD. Alternatively, a therapeutically effectiveamount is sufficient to cause an improvement in a clinically significantcondition or parameter (according to the attending physician employingone or more of the foregoing sets of criteria) associated with SDAT inan individual in need thereof.

A “responder” is defined as a patient for whom the change from baseline(Visit 2) to Week 24 in ADAS-cog is less than or equal to −4. Aresponder in terms of CIBIC-plus is defined as a patient for whomCIBIC-plus equals to “Markedly improved”, or “Moderately improved”, or“Minimally improved”, or “no change” at Week 24.t

An “adverse event” (AE) is determined according to the World HealthOrganization (WHOART, Version 1998/Q4) Dictionary. An AE occurringduring the double-blind treatment period was considered a treatmentemergent AE (TEAE) if it was not present prior to the start ofdouble-blind study medication, or if it was present prior to the startof double-blind study medication but increased in severity during thedouble-blind treatment period. An AE which occurred more than 30 daysafter the date of the last double-blind study medication (AE startdate—the last double-blind study medication date>30), was not counted asa TEAE. A “serious adverse event” (SAE) is one that results in death, isan immediate threat to life, requires inpatient hospitalization, orresults in persistent or significant disability/incapacity.

The “cortical and subcortical” regions of the brain include but are notlimited to the orbital cortex; posterior cingulated; retrosplenial andposterior parahippocampal gyrus; superior temporal gyrus; visualcortices; dorsolateral prefrontal cortex; posterior thalamus; cerebellarcortex; right temporal pole and middle temporal gyrus; right medialthalamus; left putamen; right superior parietal and right premotorcortex, left motor cortex; right insula; limbic structures such as thelateral amygdale, orbital cortex; the border between the parahippocampalgyrus and medial fusiform gyrus; anterior temporal lobe; anterior andposterior attentional system; the premotor, inferior parietal(language-related) temporal tip; and orbital and dorsal prefrontalcortices.

The terms “bilateral” or “bilaterally” refer to both sides of the brainbeing included, or regions thereof, while the term “unilateral” or“unilaterally” refer to only one side of the brain.

“FDG PET” refers to a computerized image used to quantify changes inmetabolic activity of body tissues.

The “glucose metabolic rate (GMR)” refers to how rapidly the brainmetabolizes glucose. The brain represents approximately 2% of the body'stotal weight yet accounts for 20% of the body's total oxygen utilizationand 65% of its glucose needs (Lundgren (ed.) Acute neuroscience nursing:concepts and care. Boston: Jones & Bartlett, 1986). Different brainstructures have different metabolic needs. The gray matter of the brain,particularly the frontal lobes, has the highest metabolic requirements.The metabolic rates of the occipital, parietal, and temporal lobes alongwith the basal ganglia and cerebellum are lower. The brainstem has thelowest metabolic need.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error or variation for the quantity measured given the natureor precision of the measurements. Typically, degrees of error orvariation are within 20 percent (%), preferably within 10%, and morepreferably within 5% of a given value or range of values. Numericalquantities given herein are approximate unless stated otherwise,.meaning that the term “about” or “approximately” can be inferred whennot expressly stated.

Formulation, Dosage, and Administration

Memantine (NAMENDA®) is commercially available as the hydrochloridesalt. According to the present invention, the dosage form of memantinemay be a solid, semisolid or liquid formulation. Formulation ofmemantine in semi-solid or liquid form is within the skill of the art,as the active ingredient is highly soluble in aqueous media. Usually theactive substance, i.e., memantine, will constitute between 0.1 and 99%by weight of the formulation, more specifically between 0.5 and 20% byweight for formulations intended for injection and between 0.2 and 50%by weight for formulations suitable for oral administration.

The pharmaceutical formulation comprises the active ingredients,optionally in association with pharmaceutically acceptable adjuvants,diluents, excipients and/or inert carriers.

To produce pharmaceutical formulations of the combination of theinvention in the form of dosage units for oral application, the selectedcompounds may be mixed with a solid excipient, e.g., lactose,saccharose, sorbitol, mannitol, starches such as potato starch, cornstarch or amylopectin, cellulose derivatives, a binder such as gelatineor polyvinylpyrrolidone, disintegrants, e.g., sodium starch glycolate,cross-linked PVP, cross-carmellose sodium and a lubricant such asmagnesium stearate, calcium stearate, polyethylene glycol, waxes,paraffin, and the like, and then compressed into tablets. If coatedtablets are required, the cores, prepared as described above, may becoated with a concentrated sugar solution which may contain e.g., gumarabic, gelatine, talcum, titanium dioxide, and the like. Alternatively,the tablets can be coated with a polymer known to the man skilled in theart, wherein the polymer is dissolved in a readily volatile organicsolvent or mixture of organic solvents. Dyestuffs may be added to thesecoatings in order to readily distinguish between tablets containingdifferent active substances or different amounts of the activecompounds.

For the formulation of soft gelatin capsules, the active substances maybe admixed with e.g., a vegetable oil or poly-ethylene glycol. Hardgelatin capsules may contain granules of the active substances usingeither the above mentioned excipients for tablets e.g., lactose,saccharose, sorbitol, mannitol, starches (e.g., potato starch, cornstarch or amylopectin), cellulose derivatives or gelatin. Also liquidsor semisolids of the drug can be filled into hard gelatin capsules.

Unit dosage formulations for oral administration may be provided ine.g., blister packs. Memantine tablets are available in blister packagesof 50 or 100 tablets.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstances in a mixture with a neutral fatty base, or gelatin rectalcapsules comprising the active substances in admixture with vegetableoil or paraffin oil. Liquid formulations for oral application may be inthe form of syrups or suspensions, for example solutions containing fromabout 0.2% to about 20% by weight of the active substances hereindescribed, the balance being sugar and mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid formulations maycontain coloring agents, flavoring agents, saccharine andcarboxymethyl-cellulose as a thickening agent or other excipients knownto a person skilled in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substances, preferably in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

Suitable daily doses of the memantine for the therapeutic treatment ofhumans are about 0.01-10 mg/kg bodyweight on peroral administration and0.001-10 mg/kg bodyweight on parenteral administration.

In one embodiment, 5 or 10 mg film-coated tablets to be administeredtwice a day for a dosage range of 10-40 mg/day. However, lower andhigher dosages can be and have been administered within the range of5-100 mg/day and the broader range of 5-150 mg/day.

In a preferred embodiment, memantine will be administered within therange from about 5 mg to about 100 mg per day, preferably, from about 10to about 40 mg per day, more preferably about 20 mg/day.

However, for any pharmaceutical composition used in the method of theinvention, the therapeutically effective dose can be estimated initiallyfrom animal models to achieve a circulating plasma concentration rangethat includes the IC₅₀ (i.e., the concentration of the test compoundwhich achieves a half-maximal inhibition of NMDA receptor activity inthe relevant areas of the brain). Dose-response curves derived fromanimal systems are then used to determine testing doses for the initialclinical studies in humans. In safety determinations for eachcomposition, the dose and frequency of administration should meet orexceed those anticipated for use in the clinical trial.

Other factors to consider are the dosage procedure, the conditions of apatient or a subject animal such as age, body weight, sex, sensitivity,feed, dosage period, drugs used in combination, seriousness of thedisease. The appropriate dose and dosage times under certain conditionscan be determined by the test based on the above-described indices butmay be refined and ultimately decided according to the judgment of thepractitioner and each patient's circumstances (age, general condition,severity of symptoms, sex, etc.) according to standard clinicaltechniques.

Toxicity and therapeutic efficacy of the compositions of the inventioncan be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it can be expressed as the ratio ED₅₀/LD₅₀.Compositions that exhibit large therapeutic indices are preferred.

Treatment duration can be short-term, e.g., several weeks (for example10-14 weeks), or long-term until the attending physician deems furtheradministration no longer is necessary to obtain a benefit.

EXAMPLES

The invention is also described by means of particular examples.However, the use of such examples is illustrative only and in no waylimits the scope and meaning of the invention or of any exemplifiedterm. Likewise, the invention is not limited to any particular preferredembodiments described herein. Indeed, many modifications and variationsof the invention will be apparent to those skilled in the art uponreading this specification and can be made without departing from itsspirit and scope. The invention is therefore to be limited only by theterms of the appended claims along with the full scope of equivalents towhich the claims are entitled.

Example 1 Randomized, Placebo-Controlled, Double-Blind Study ofMementine for the Treatment of Mild-to-Moderate Alzeimer's Disease

The study consisted of 1-2 weeks of single-blind placebo treatmentfollowed by 24 weeks of double-blind treatment. Results were evaluatedover seven clinical visits; at initial screening, baseline, and the endof weeks 4, 8, 12, 18 and 24.

Patient Population and Diagnosis. The study population consisted ofoutpatients who were at least 50 years old and were diagnosed withprobable AD at screening according to the NINCDS-ADRDA criteria. Thesecriteria consist of the following:

dementia established by clinical exam and by the MMSE and furtherconfirmed by neurological tests

deficits in 2 or more areas of cognition

progressive worsening of memory and other cognitive functions

no disturbance of conscience

onset between the ages of 40-90

absence of systemic diseases, such as cardiovascular diseases, thatcould explain the cognitive changes

Supportive Criteria Include:

progressive deterioration of specific cognitive functions such aslanguage, motor skills, and perception (aphasia, apraxia, agnosia,respectively).

impaired activities of daily living

positive family history, particularly if documented neuropathologically.

lab results: normal lumbar puncture, EEG, and evidence of cerebralatrophy on CT or MRI

Clinical Features May Also Include:

plateaus in clinical course

associated symptoms: depression, insomnia, incontinence, delusions,illusions, hallucinations, catastrophic verbal, emotional or physicaloutbursts, sexual disorders, and weight loss;

increased motor tone, myoclonus or gait disorder

seizures

normal CT for age

These criteria also include inventories such as the Hachinski scale(Rosen et al., Ann Neurol. 1980; 7(5):486-8-ischemia, ≦4), Montgomeryand Asburg Depression Rating Scale (MADRS-<22 at screening), and theMMSE described below. Confirmatory CT or MR scans were also conductedwithin 12 months of entry. Informed consent was obtained by the patient,caregiver or legal representative prior to initiation. A completephysical, and blood and urine samples were also obtained at screening.

The population of patients who received at least one dose ofdouble-blind memantine, and completed at least one post-baselineefficacy evaluation of either the ADAS-cog or the CIBIC-plus isdesignated the “intent-to-treat” (ITT) population. The population ofrandomized patients who received at least one dose of double-blind studymedication is designated the “safety population”. The randomizedpopulation designates all patients randomized into the study.

Patient population and baseline characteristics are presented in Table 1below: TABLE 1 Trial and Baseline Characteristics (Safety Population)Placebo Memantine Overall Population, n Randomized 202 201 403Safety(Treated) 202 201 403 Intent-to-Treat 198 196 394 Dropout, %Overall 17.30% 17.90% 17.60% Dropout due to AE  5.0%  9.50%  7.20% Age(Years) Mean 77 78 77.5 Median 78 79 79 Range 51-95 53-92 51-95 BaselineMMSE ≦ 22 Mean 17.2 17.4 17.3 <=14, n 49 50 99 >14, n 153 151 304Interventions

Patients were assigned to double-blind treatment for 24 weeks precededby a 7-14 day single-blind placebo lead-in period. The lead-in periodwas solely for the purpose of assessing compliance. Patients wererandomized to memantine or placebo groups in permuted blocks of four inaccordance with the randomization list. At the baseline visit, patientswere sequentially assigned the randomization numbers. No individualpatient randomization code was revealed during the trial. Treatmentcodes were unblinded at the termination of the study after the databasewas locked.

This study was conducted as a fixed-dose study. All patients assigned tothe memantine group received an initial dose of 5 mg per day; the dosewas titrated in 5 mg weekly increments to a final dose of 20 mg/day(administered as two 5 mg tablets twice a day). Study drug was providedas blister packs containing masked study medication such that placeboand memantine tablets were visually identical, and all patients receivedfour tablets of study medication daily (in combinations of memantine 5mg tablets and matching placebo tablets). Transient dose adjustmentswere permitted between weeks 3 and 8 for patients experiencingdose-limiting adverse events. However, all patients were required toreceive the target dose of 20 mg/day by the end of week 8. Patients notable to tolerate the target dose by week 8 were discontinued from thestudy.

No other NMDA-receptor antagonist was administered as a concomitantmedication by the patient population.

Statistical analysis. For primary efficacy measurements, (e.g., changefrom Baseline (visit 2) to Week 24 in the total ADAS-cog scores from theITT population) the comparison between memantine and placebo wereperformed using two-way analysis of covariance (ANCOVA) with treatmentgroup and center as the two factors, and the baseline scores ascovariate. Both the Last Observation Carried Forward (LOCF) imputationapproach and the Observed Cases (OC) approach were performed at week 24.

The CIBIC-plus rating was analyzed using the CMH test, controlling forstudy center (35 total centers). Descriptive statistics were calculatedby visit.

For secondary efficacy measurements, the comparison between memantineand placebo was performed using two-way analysis of covariance (ANCOVA)with treatment group and center as the two main effects, and thebaseline scores as covariate. Descriptive statistics were calculated byvisit. Again, all analyses were performed using both the LastObservation Carried Forward (LOCF) imputation approach and the ObservedCases (OC) approach.

Results of ANCOVA were summarized using least square (LS) means for eachtreatment group with corresponding standard error (SE), thebetween-treatment (2-24 week) difference in the least square means withcorresponding 95% confidence interval, and the between-treatment p-valuecorresponds to the SAS Type III sum of squares.

RESULTS

Efficacy. Statistical improvements in the primary efficacy parameters ofADAS-org and CIBIC-plus were achieved by LOCF analysis in the ITTpopulation, with a p value of 0.003 and 0.004, respectively. See Table 2below: TABLE 2 Efficacy at Week 24 (ITT Population) LOCF Analysis OCAnalysis Difference* p-value Difference* p-value ADAS-cog −1.9 0.003−1.1 0.130 CIBIC+ −0.32 0.004 −0.26 0.030 ADCS-ADL 0.1 0.890 0.0 0.975NPI total −3.5 0.011 −2.1 0.143*memantine minus placebo, based on mean value for CIBIC+, and LS Meanvalue for ADAS-cog, ADL, and NPI-total

Notably, as determined by CIBIC-plus and LOCF analysis in the ITTpopulation, of 196 patients randomized to memantine, 9 demonstrated“marked improvement” and 27 demonstrated “moderate improvement comparedwith 7 and 21 in the population randomized to placebo (198). Similarly,18 and 1 of the memantine-treated population, demonstrated moderateworsening or marked worsening, respectively, compared with 34 and 3,respectively, of the placebo-treated group (data not shown). By OCanalysis, 8 memantine-treated patients exhibited moderate improvementand 24 exhibited minimal improvement, compared with 7 and 19 patients,respectively, in the placebo-treated population. In addition, 1memantine-treated patient demonstrated marked worsening compared to 3 inthe placebo group, and 17 memantine-treated patients compared with 27placebo-treated patients showed moderate worsening (data not shown).

The population of CIBIC-plus and ADAS-cog responders was compared tothat of the non-responders to evaluate the placebo effect. As shown inTable 3, below, CIBIC-plus analysis according to LOCF demonstrated that100 patients who were designated responders received the placebo, while132 received memantine, and 97 reported “non-responders” receivedplacebo, while only 64 non-responders received memantine. Similarresults with OC analysis were obtained from CIBIC-plus, where 85“responders” received placebo and 108 received memantine, and 81“non-responders received placebo and 56 received memantine. TABLE 3CIBIC+ and ADAS-cog Responders at Week 24 (ITT Population) LOCF AnalysisOC Analaysis Pla/Mem p-value Pla/Mem D-value CIBIC+ Responder 100/1320.001  85/108 0.007 Non-Responder 97/64 81/56 ADAS-cog Responder 40/470.352 33/34 0.846 Non-Responder 158/148 129/126Note: Responder in ADAS-cog: change from baseline in total ADAS-cog <=−4 Responder in CIBIC +: CIBIC + ratings = 1, 2, 3, 4 (no change orimprovement)

Of the safety patient population, about 66% had previously taken atleast one medication prior to this study (no patients had beenadministered any anti-dementia medication for one month prior tocommencement of this study). Of those, about 69% of the placebo-treatedand 62% of the memantine-treated patients had been on previous dementiamedication. Of those, about 65% of the placebo-treated and 59% of thememantine-treated individuals had used an AChEI such as donepezil,galantamine, or rivastigmine, These results show memantine was effectivefor individuals with mild-to-moderate SDAT in whom prior treatment withother anti-dementia drugs, notably AChEIs has been discontinued.

Results were shown as early as week 8, by LOCF, when the LS mean changeof the placebo-randomized group, measured using ADAS-cog, was 0.2 andthat of the memantine-randomized group was −1.2 (p value of 0.003). Byweek 12, the LS mean was −0.1 for the placebo-treated group and −1.4 forthe memantine-treated group (p=0.009).

OC measurements of ADAS-cog also showed significant improvement by week8 in the memantine-treated population, where the LS mean was −1.1compared to that of 0.2 for the placebo (p=0.006).

Similarly for CIBIC-plus, statistically significant improvement in thememantine-treated group compared with the placebo was achieved by week12 using LOCF and OC.

For NPI Total, significance using LOCF was achieved by week 24. Of theindividual NPI criteria, three were significantly better in thememantine-treated compared with the placebo-treated group. Achievementof statistical significance in total NPI score is attributed to asub-threshold benefit in several criteria, not only to the threecriteria that showed significant change individually.

The failure to observe a statistically significant change in ACDS-ADLmay have been due to the particular selection of the 23 questions orsimply to the fact that this type of patient population(mild-to-moderate AD) does not yet display severe deterioration in thevarious symptoms that make up the evaluation criteria. In any event, aprior failure of a clinical study to show that memantine conferred anyadditional benefit over donepezil in patients with mild-to-moderate AD(especially after success of a similar study in moderate-to-severe ADpatients) would have discouraged those skilled in the art from usingmemantine in the mild-to-moderate population.

Each of the foregoing considerations and all of them make the presentclinical results unexpected.

Example 2 The Effects of Memantine on Brain Glucose Metabolism inMild-to-Moderate Alzehimer's Disease METHODS

Drug treatment. As stated above, patients were randomized to receive 20mg/day (10 b.i.d.) memantine or placebo for 24 weeks. PET scans wereperformed for 10 (5 receiving memantine and 5 receiving placebo)patients at baseline and at the end of week 24.

PET Scan Acquisition. Subjects were PET scanned at the University ofCalifornia, Irvine Brain Imaging Center using a GE 2048-15B dedicatedhead scanner. Thirty slices at 6.5-mm intervals (15 in each of two sets)were obtained so as to cover the entire brain. Attenuation correctionwas performed by obtaining a transmission scan using a ⁶⁸Ge pin source.A thermosetting plastic facemask was used to hold the subject stationaryduring the 60 minutes of total image acquisition. Scans werereconstructed with a blank and a transmission scan. PET image count wasused for study analyses and adjusted for intrasubject global differencesusing normalization (proportional scaling).

PET Image Methodology and Analysis. Differences in regional FDG uptakewere analyzed using SPM99 software (Wellcome Department of CognitiveNeurology, London, UK), implemented on the Matlab platform (MathWorksInc., Sherborn, Mass.). Statistical parametric maps (SPMs) are spatiallyextended statistical processes that are constructed to test hypothesesabout regionally specific effects in neuroimaging data. Statisticalparametric mapping combines the general linear model and the theory ofGaussian random fields to make statistical inferences about regionaleffects. The images were spatially normalized using a twelve parameteraffine transformation, estimated by minimizing the residual sum ofsquares between each scan, and a reference or template image conformingto the standard space defined by Talairach and Tournoux. The originalimage matrix obtained at 256×256×30 with a voxel size of 4.5 mm×4.5mm×6.5 mm plane separation where transformed and resliced to a 79×95×68matrix with a voxel size of 2 mm×2 mm×2 mm plane separationcorresponding more closely to the Talairach standard anatomical space,and were smoothed using an (5 mm FWHM) isotropic Gaussian kernel. Priorto statistical inference, images were scaled to a canonical normal toaccount for global variations between subjects over time (proportionalscaling).

To test the hypotheses regarding regionally specific condition effects,the estimates were compared using linear contrasts. The resulting set ofvoxel values for each contrast represents a parametric mapping of thet-statistics, SPM(t), which were transformed into the unit normaldistribution SPM(z) and thresholded at p<0.025 uncorrected. Theresulting foci were then characterized in terms of peak height (u). Thesignificance of each region was estimated based on the probability thatthe observed peak height could have occurred by chance P(Z_(max)>u).Because the maximum intensity and the spatial extent of a region above uare not independent, a simple “Bonferroni” correction for multiplecomparisons would be inappropriate. Accordingly, spatial extentthresholding based on the Gaussian random field theory was performed at10 voxels to correct for multiple comparisons.

Anatomical localization of significant regions was accomplished throughcomparison with the Talaraich and Tournoux atlas and confirmation by aneuroanatomist who was blind to group assignments. The Talairach andTournoux coordinates are provided in parentheses following the relevantbrain regions. It should be noted, however, that present PET imagingtechnology does not allow for precise anatomical localizations tospecific subcortical nuclei and sublobular cortical areas. Someapproaches have applied co-registration within individual MRI templatesin order to aid in verifying anatomical localization. Such templateswere not available in this study. The interpretation by blindedneuroanatomist aided in anatomical verification by employing dynamicinterpretation of brain circuits based on known anatomical structuresand following changes in regional metabolism between adjacent slices.

Snodgrass Picture Naming Task. Several studies of semantic abilities indementia of the Alzheimer Type suggest that their semantic abnormalitiesmay affect certain categories of knowledge. In the present invention,all patients who were subjected to PET scanning were evaluated duringimaging using the Snodgrass picture naming activation task, The use of atask during the FDG uptake was used to image increases in thehippocampus and temporal lobe. This Snodgrass Picture Naming activationtask was sensitive to object naming, which is impaired in mild tomoderate AD. The Snodgrass picture naming activation task andperformance analysis was based, in part, on the speed of identificationand articulation of the name that corresponds to a set of 260 pictures(Snodgrass and Vanderwart, J. Experimental Psychology: Human Learningand Memory 1980; 6(2): 174-215). The pictures are black-and-white linedrawings executed according to a set of rules that provide consistencyof pictorial representation. The pictures were standardized on fourvariables of central relevance to memory and cognitive processing:

RESULTS

In the placebo vs. baseline condition (FIG. 1), most of the changes aredecreases in GMR bilaterally throughout cortical and subcorticalregions. These include bilateral decreases in orbital cortex, posteriorcingulate, retrosplenial, and posterior parahippocampal gyrus, superiortemporal gyrus, visual cortices, dorsolateral prefrontal cortex,posterior thalamus, and cerebellar cortex. Unilateral decreases wereobserved in the right temporal pole and middle temporal gyrus, rightmedial thalamus, left putamen, right superior parietal and rightpremotor cortex, left motor cortex, and right insula. Limited increaseswere demonstrated in limbic structures such as the lateral amygdala,orbital cortex, and the border between the parahippocampal gyrus andmedial fusiform gyrus, and anterior temporal lobe.

In the memantine-treated patients (FIG. 2), metabolic increases wereobserved bilaterally throughout the CNS, including the cerebral cortex,cerebellum, and brainstem. In the cerebral cortex, greater increases arefound in the right hemisphere, as well as bilaterally in the orbitalcortex, visual cortices, superior and inferior parietal cortex,posterior cingulate, retrosplenial cortex and posterior parahippocampalgyrus, medial prefrontal and anterior cingulate cortices, premotorcortex, and dorsal prefrontal cortex. Subcortically, increases werepresent over a broad region of the left pontine nuclei, the righttectum, left subthalamic nucleus/red nucleus region, and right putamen.An isolated region of the left visual cortex and left putamen exhibiteddecreases in glucose metabolism.

Regarding the Snodgrass picture naming activation task,memantine-treated subjects were able to perform the task at better thanchance. There was no significant difference in Snodgrass performancebetween the two treatment groups.

DISCUSSION

In this pilot study, it was shown that the placebo-treated patientsgenerally showed expected metabolic decreases in most cortical areasover the 24-week period. There were also mild metabolic increases insome limbic areas (e.g., orbital cortex and anterior temporal lobestructures, as has previously shown (Potkin et al., Int JNeuropsychopharmacol. 2001; 4(3):223-30). In the medial occipitalcortex, some metabolic decreases were also observed in theplacebo-treated patients in the present study. This is in contrast tomild metabolic increases in the occipital pole observed in our previousstudy. The metabolic changes observed in the placebo-treated patientswere consistent with decreased functioning of the attentional system,especially the posterior attentional system (tectum, posterior thalamus,posterior cingulate, and superior parietal lobule and precuneus).

An entirely different pattern was observed in the memantine-treatedsubjects. In general, the areas that showed statistically significantdecreases in the placebo-treated patients showed metabolic increase.These areas of increased metabolism following memantine include corticalstructures of the anterior and posterior attentional system, as well aspremotor, inferior parietal (language-related), temporal tip, andorbital and dorsal prefrontal cortices. In addition, isolated increaseswere found unilaterally in the tectum as well as basalganglia/extrapyramidal structures (pontine nuclei, subthalamic/rednucleus region, putamen, and cerebellum).

The use of PET to document the effects of treatment has distinctadvantages in being able to examine regional changes in brain metabolismover time. These measures offer advantages over current diagnosticmeasures, e.g. CIBC-Plus and ADAS-cog. For example, the CIBIC-Plus isdependent on caregiver observations, which may be affected byfluctuating caregiver capacity. FDG PET overcomes some of theselimitations.

In addition, all subjects were able to perform the Snodgrass PictureNaming activation task at better than chance; therefore, the task didnot suffer from either floor or ceiling effects, unlike many memorytasks. This feature of the test procedure guards against motivationapathy and discouragement as factors interfering with performance. Therewas no significant difference in Snodgrass performance; therefore,performance does not explain the observed findings.

Memantine, a noncompetitive NMDA antagonist with demonstrated efficacyin patients with moderate to severe AD, was also effective for thetreatment of mild-to-moderate AD, and can reverse the expected metabolicchanges associated with regression in AD.

1. A method for treating mild-to-moderate Alzheimer's disease comprisingadministering to a subject in need thereof an effective amount ofmemantine or a pharmaceutically acceptable salt thereof.
 2. The methodof claim 1, wherein memantine is administered in a dose ranging fromabout 5 to about 100 mg/day.
 3. The method of claim 2, wherein the doseis about 10 mg to about 40 mg/day.
 4. The method of claim 1, wherein thesubject is selected from the group consisting of naive subjects andsubjects who had previously been treated with an acetylcholinesteraseinhibitor (AChEI) but had discontinued ACHEI therapy no later than oneday prior to commencement of memantine administration.
 5. The method ofclaim 1, wherein the treatment is determined by improvement or nodeterioration, or slower than expected deterioration in at least one ofthe assessments selected from the group consisting of the Alzheime'sDisease Assessment Scale-cognitive subscale (ADAS-cog), the Alzheimer'sDisease Cooperative Study-Activities of Daily Living (ADCS-ADL)Inventory and Clinician's Interview-Based Impression of Change PlusVersion (CIBIC-plus).
 6. A method for inhibiting the reduction ofglucose metabolism associated with regression in subjects withmild-to-moderate Alzheimer's disease, comprising administering to asubject in need thereof an effective amount of memantine or apharmaceutically acceptable salt thereof, in a pharmaceuticallyacceptable carrier.
 7. The method of claim 6, wherein the prevention ofreduction of glucose metabolism occurs in the cortical and subcorticalregions of the subject's brain.
 8. The method of claim 7, wherein theinhibition of reduction of glucose metabolism occurs unilaterally orbilaterally.
 9. The method of claim 7, wherein the inhibition ofreduction of glucose metabolism occurs bilaterally in one or more of theregions selected from the group consisting of the anterior and posteriorattentional system, the premotor, the inferior parietal, temporal tip,and the orbital and dorsal prefrontal cortices.
 10. The method of claim8, wherein the prevention-of reduction of glucose metabolism occursbilaterally in one or more of the regions selected from the groupconsisting of the tectum the pontine nuclei, the subthalamic/red nucleusregion, the putamen, and the cerebellum.
 11. The method of claim 6,wherein memantine is administered in a dose ranging from about 5 toabout 100 mg/day.
 12. The method of claim 11, wherein the dose is about10 mg to about 40 mg/day.
 13. The method of claim 12, wherein the doseis about 20 mg/day (10 mg b.i.d.).
 14. A method for treating mildAlzheimer's disease comprising administering to a subject in needthereof an effective amount of memantine or a pharmaceuticallyacceptable salt thereof.
 15. The method of claim 14, wherein memantineis administered daily in a dose ranging from about 5 to about 100mg/day.
 16. The method of claim 15, wherein the dose is about 10 mg toabout 40 mg/day.
 17. The method of claim 14, wherein the treatment isdetermined by the improvement, or reduction or arrestation ofdeterioration in at least one of the assessments selected from the groupconsisting of the Alzheimer's Disease Assessment Scale-cognitivesubscale (ADAS-cog), the Alzheimer's Disease CooperativeStudy-Activities of Daily Living (ADCS-ADL) Inventory and Clinician'sInterview-Based Impression of Change Plus Version (CIBIC-plus).